The aim of the HERITAGE Family Study is to document the cardiovascular and metabolic responses to endurance training, and the contribution of genetic factors to the concomitant response of cardiovascular disease (CVD), and type 2 diabetes risk factors. In Phase 1 (1992-1997), 855 sedentary subjects from 218 families were recruited and 742 subjects (483 Whites from 99 families, 259 Blacks from 105 families) completed a standardized 20-week exercise-training program. During Phase 2 (1997-2001), a series of non-genetic studies on determinants of cardiorespiratory endurance, and CVD and type 2 diabetes risk factors in the sedentary state and in the response to training were undertaken. Genetic analyses focused on the determination of the heritability levels, and testing for paternal or maternal effects, major gene effects and segregation patterns. A panel of candidate genes was typed for association and linkage studies. A genome-wide scan was performed for the training response of cardiorespiratory endurance and CVD and type 2 diabetes risk factors. The proposed Phase 3 is organized around five specific aims. First, genetic epidemiology questions pertaining to training-related changes in major CVD risk factors will be investigated with special emphasis on Black and White differences. Second, the search for genes and mutations will continue utilizing four strategies: extension of the genome-wide scan including targeted dense SNPs mapping, extension of the skeletal muscle gene expression studies with SAGE, use of the AFLP technique and use of novel statistical methods such as multivariate linkage methods, subgroup analyses, and total genome-wide linkage tests. Third, the genetic and non-genetic determinants of insulin sensitivity, insulin secretion and glucose effectiveness in response to training will be investigated using LONGMOD, an extension of MINMOD currently in development to model longitudinal data more efficiently. Fourth, the nongenetic determinants of the targeted CVD risk factors and their responses to endurance training will be investigated, with emphasis on Black and White differences. Fifth, we will assess whether a closely supervised 20-week period of regular exercise had any long-term effects on habitual physical activity levels and health status. The findings from Phase 3 of the HERITAGE Family Study will provide unique information on the benefits of a physically active lifestyle and on the determinants of the high and low response phenotypes in Blacks and Whites.